Intermediates for the production of 19-norhydrocortisone



United States Patent INTERMEDIATES FOR THE PRODUCTION OF 19-NORHYDROCORTISONE Barney J. Magerlein, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application August 21, 1956 Serial No. 605,409

10 Claims. (Cl. 260-23955) This invention relates to steroid chemistry and is more particularly concerned with novel processes for the production of the physiologically active steroid hormone l9-norhydrocortisone from steroids having an aromatic A-ring and to certain novel compounds produced thereby. It is an object of the present invention to provide the novel processes and compounds described herein which are useful in the production of l9-norhydrocortisone. Other objects and uses will be apparent to one skilled in the art.

The process of this invention, illustrated by the following equation wherein R is an ether radical is a cyclic ketal radical, and AcO is an acyloxy radical, comprises: chemically reducing the A-ring of B-etherified 3,ll,B,l7oc,21 tetrahydroxy 19 nor 1,3,5(10) pregnatrien-ZO-one 20-cyclic ketal (II) with lithium, an alcohol, and liquid ammonia to produce 3-etherified 3,11fi,17oc,21 tetrahydroxy 19 nor 2,5(10) pregnadien-ZO-one 20-cyclic ketal (III); and hydrolyzing the 3-ether radical and the ZO-cyclic ketal radical and isomerizing the 2- and 5(l0)-double bonds of the thusproduced diene by reacting with a hydrolyzing agent to produce 1 1fi,17a,21-trihydroxy-19-nor-4-pregnene-3,20-dione, i.e. l9-norhydrocortisone (IV). The conversion of 3-etherified 3,11/3,17a,21-tetrahydroxy 19 nor 2,5(10)- pregnadien-20-one 20-cyclic ketal (III) to 19-norhydrocortisone (IV) preferably is accomplished in one step by heating with an acid hydrolyzing agent. This conversion also is accomplished by reacting the S-etherified 3,115, 170:,21 tetrahydroxy 19 nor 2,5 (10) pregnadien- 20-one 20-cyclic ketal (III) with an acid hydrolyzing agent at CH3 CH3 0112011 onion =0 o=o ----0H ---0H HO AGO j 1 ice ona on,

CHIOH CHQOH O O "-03 --OH HO AcO II H) CH CH CHQOH CH OE HO HO III IIIa CHzOH CHzOH )R ---OH OH HO H0 IV IIIb about room temperature to hydrolyze the 3-ether radical and isomerize the 2-double bond and produce 11/i,17u,21- trihydroxy-19-nor-5(10)-pregnene-3,20-dione 20 cyclic ketal (IIIa) reacting the thus-produced 3-keto compound with a base to isomerize the 5(10)-double bond and produce 1 1B,17a,21-trihydroxy-19-nor-4-pregnene-3,ZO-dione 20-cyclic ketal (IIIb); and heating the thus-produced 4-pregnene with an acid hydrolyzing agent to hydrolyze the 20-cyclic ketal radical and produced 19-norhydro-, cortisone (IV).

The starting 3-etherified 3,1lfi,17a,21-tetrahydroxy-19- nor-1,3,5(10)-pregnatrien-20-one 20-cyclic ketal (II) preferably is obtained by ketalizing the 20-keto group in S-etherified 3,11 8,17a,21-tetrahydroxy-19-nor-1,3,S( 10)- pregnatrien-20-one (I) by heating with a glycol in the presence of an acid catalyst. The starting 3-etherified 3,11/3,17a,21 tetrahydroxy 19 nor 1,3,5(10) pregnatrien-ZO-one 20-cyclic ketal (II) also is obtained by ketalizing the ZO-keto group'in 3-etherified llfl-acyloxy- 3,17u,21 trihydroxy 19 nor 1,3,5(10) pregnatrien- 20-one (Ia) by heating with'a glycol in the presence of an acid catalyst followed by reductively hydrolyzing the 11,8-acyloxy radical in the thus-obtained 20-cyclic ketal (Ib) with a metal hydride to produce 3-etherified 3,1119, 170:,21 tetrahyclroxy 19 nor 1,3,5 pregnatrien- 20-one ZO-cyclic ketal (II). Both 3-etherified 3,11,B,l7or, 21 tetrahydroxy 19 nor 1,3,5(10) pregnatrien 20- =one (I) and the llfi-acyloxy compound thereof (Ia) are obtained as described in our copending application Serial No. 605,411, filed August 21, 1956.

In the processes of the present invention the exact nature of the ether radical (R 0 in the foregoing equation) and acyloxy radical (AcO in the foregoing equation) is immaterial, but generally said ether and acyloxy radicals each contain less than twelve carbon atoms. Preferably said radicals are hydrocarbon acyloxy [hydrocarbon-O-l and hydrocarbon acyloxy ll [hydrocarbon- OO] radicals, respectively, each containing less than twelve carbon atoms. In an especially preferred embodiment of this invention said radicals are alkoxy and alkanoyloxy radicals, respectively, each containing less than nine carbon atoms. The most preferred embodiment of said radicals are methoxy and acetoxy, respectively. Illustrative ether radicals are methoxy, ethoxy, propoxy, butyroxy, valeroxy, hexoxy, heptoxy, octanoxy, B-trichloro-a-acetylethoxy, chlorornethoxy, ;8-hydroxyethyleneoxy, dimethylmethoxy, diethylmethoxy, isobutyroxy, isovaleroxy, ot-tetrahydropyranyloxy, 0c and fi-naphthyloxy, cyclohexyloxy, cyclopentyloxy, [3,;3-dicarbethoxyethenyloxy, B-ketocyclohexenyloxy, afi-dimethylethoXy, 0;,[3- and ,8,B-diethylethoxy, benzoxy, ortho, meta and paratolyloxy, a and fl-phenylethyloxy, 8-indolyloxy, afuryloxy, cc and B-cyclohexylethyleneoxy, ortho, meta and para-nitrobenzoxy, ortho, meta and para-aminobenzoxy, etc. Illustrative acyloxy radicals are those containing acyl radicals of the acids formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2- methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, optically active abietic, u-ethylisovaleric, cyclopropylideneacetic, cyclopentylformic, cyclopentylacetic, oz and fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, a and B-cyclohexylpropionic, benzoic, 2, 3 or 4-methylbenzoic, 2,3- 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, ot-naphthoic, 3 -methyl -lx-naphthoic, phenylacetic, 0c and B -phenylpropionic, diphenylacetic, triphenylacetic, succinic, glutaric, a-methylglutaric, fl-methylglutaric, 5,;3-dimethylglutaric, adipic, pimelic, suberic, glycolic, lactoic, citric, tartaric, d-maleic, d-glyceric, malonic, gluconic, salicyclic, glycine, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, para-aminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifiuoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, a-naphthoxyacetic, B-pyrrolidylpropionic, carbamic acid, phenylcarbamic, n-butylcarbamic dimethylcarbamic, diethylcarbamic, allophanic, B-furylcarboxylic, N-methylpyrrolidyl-Z-carboxylic, a picolinic, indole-Z-carboxylic, 6-hydroxyind0lyl-3-acetic, N-methylmorpholyl-Z-carboxylic, pyrrolyl-Z-carboxylic, etc. Likewise the exact nature of the cyclic ketal radicals 0 A in the foregoing equation) is immaterial, but generally they are ufiand n y-glycol radicals 4 respectively) i.e. are radicals of glycols having less than two carbon atoms between its carbinol radicals containing less than twelve carbon atoms. Preferably said radicals are hydrocarbon a-glycol radicals containing less than twelve carbon atoms. In an especially preferred embodiment of this invention the cyclic ketal radical is an 1,2-dihydroxyalkane radical containing less than nine carbon atoms. The most preferred cyclic ketal radical is the ethylene glycol radical. Illustrative cyclic ketal radicals are ethylene glycol, 1,2-propylene glycol, trimethylene glycol, 1,2- and 1,3-butylene glycol, tetramethylene glycol, 1,2- and 1,3-pentylene glycol, 1,2- and 1,3-hexylene glycol, 1,2- and 1,3-octylene glycol, 1,2- isobutylene glycol, 1,2-isooctylene glycol, 1,2-dihydroxycyclohexane, l,Z-dihydroxycyclopentane, l-methyl-2,3- cyclopentanediol, 3-methyl-2,4-hexanediol, 1,2-octadecanediol, 1,2-decanediol, etc.

In carrying out the process of the present invention pregnatrien-ZO-one ZD-cyclic ketal (II) is chemically re duced by the Birch reduction method with lithium (or sodium), an alcohol (preferably a lower-alkanol containing less than six carbon atoms, e.g. methanol, ethanol, isopropanol, etc), and liquid ammonia to produce 3 etherified 3,11B,17a,2l-tetrahydroxy-19-nor-2,5(10)-pregnadien-ZO-one 20-cyclic ketal (III), a preferred procedure being given in Example 4. Hydrolyzing and isomerizing 3-etherified 3,1 15, 1 706,21-tetrahydroxy-19-nor-2,5 l0)- pregnadien-ZO-one 20-cyclic ketal (III) to obtain l9-norhydrocortisone (IV) is accomplished in one step (a preferred procedure being given in Example 8) by heating (suitably 65 to degrees centigrade) suitably for fifteen minutes to four hours with an acid hydrolyzing agent, e.g. the preferred fifty percent aqueous acetic acid of Example 8, or other organic acid (e.g. formic acid) or mineral acid (e.g. sulfuric acid) solution of suitable acid strength using, if necessary, an organic solvent (e.g. methanol, ethanol, dioxane, etc.) to obtain a homogeneous reaction solution, the shorter reaction periods and/or lower reaction temperatures usually being preferred when mineral acids are employed. l9-norhydrocortisone (IV) also is produced by the following threestep process. Hydrolyzing and isomerizing the 3-etheri- 3,11,8,17tx,21-tetrahydr0xy-l9-nor-2,5(10)-pregnadien-ZO-one 20-cyclic ketal (III) to produce llfl,l7e,2ltrihydroxy-l9-nor-5( 10) -pregnene-3,20-dione 20-cyclic ketal is (IIIa) accomplished by reacting with an acid hydrolyzing agent, e.g. dilute aqueous mineral acid (e.g. sulfuric acid), or organic acid of suitable acid strength, suitably at about room temperature (e.g. twenty to forty degrees centigrade) for a reaction period of from fifteen minutes to four hours using, if necessary, an organic solvent (e.g. methanol or ethanol) to obtain a homogeneous solution, a preferred procedure being given in Example 5. Reacting the 1113,1704,21-trihydroxy-19-nor- 5(l0)-pregnene-3,20-dione 20-cyclic ketal (IIIa) with base, e.g. sodium alkoxide in alcohol, alkali-metal hydroxide in alcohol, etc. suitably at about room temperature (e.g. twenty to forty degrees Centigrade) produces 11/3,17a,21 trihydroxy 19 nor 4 pregnene 3,20- dione 20-cyclic ketal (11111), a preferred procedure being given in Example 6. Hydrolyzing 1lfi,17u,Z1-trihydroxy-l9-nor-4-pregnene-3,ZO-dione 20-cyclic ketal by heating with an acid hydrolyzing agent as described previously in the conversion of compound III to compound IV produces 19-norhydrocortisone (IV), a preferred procedure being given in Example 7. The isolation and purification of the compounds of the foredescribed processes is accomplished by conventional procedures as illustrated by Examples 4 through 8.

In producing the starting 3-etherified 3,11fl,17,21-

tetrahydroxy-19-nor 1,3,5 10) -pregnatrien*20-one 20-cyclie ketal (II) the ketalization of the 20-keto group in 3"-etherified 3,11,8,17a,20-tetrahydroxy 19-nor-1,3,5(10)- pregnatrien-20-one (I) by heating with a glycol in the presence of an acid catalyst (e.g. para-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, etc.) according to conventional prior art procedure is employed, a preferred procedure being given in Example 2. The starting compound II also is prepared by ketalization, as above, of the 20-keto group in B-etherified 11,8-acyloxy-3,17a,21- trihydroxy-19-nor-1,3,5(10)-pregnatrien-20-one (Ia) to produce 3-etherified 1lfi-acyloxy-Il,17a,21-trihydroxy-l9- nor-l,3,5(10)-pregnatrien-20-one 20-cyclic ketal (Ib), a preferred procedure being given in Example 1, followed by reductively hydrolyzing the llfi-acyloxy radical in the thus-obtained 20-cyclic ketal with a metal hydride (suitably the preferred lithium aluminum hydride, etc.) using an organic solvent (e.g. ether, dioxane, ether-benzene mixture, etc.) according to conventional prior art procedure and produce 3-etherified 3,1l5,l7a,2l-tetrahydroxy-19- nor-l,3,5(10)-pregnatrien-20-one 20-cyclic ketal (H), a preferred procedure being given in Example 3. The iso-' lation and purification of the compounds of the foredescribed processes is accomplished by conventional procedures as illustrated by Examples 1 through 3.

The following examples are illustrative only and are not to be construed as limiting the scope of the present invention.

Example 1.-3 methoxy 11B acetoxy 170:,21 dihydroxy 19 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal One gram of 3-methoxy-1lp-acetoxy-l7a,21-dihydroxy- 19-nor-l,3,5(10)-pregnatrien-20-one, fifty milligrams of para-toluenesulfonic acid, and six milliliters of ethylene glycol is dissolved in 75 milliliters of benzene and heated under reflux for seventeen hours. The water formed during the course of the reaction is codistilled with the benzene. The solution ".hen is cooled, washed with dilute aqueous sodium bicarbonate solution, and chromatographed over magnesium silicate (Florisil) using acetonehexane (Skellysolve B) mixture for elution. The thuspurified product, 702 milligrams, is recrystallized from ethyl acetate to provide 590 milligrams of 3 methoxy 11B acetoxy 17a,21 dihydroxy 19 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal, melting point 214 to 218 degrees centigrade. Further recrystallized from ethyl acetate, the compound melts at 218 to 220 degrees centigrade.

Analysis.Calculated for C H O C, 67.28; H, 7.67. Found: C, 67.15; H, 7.50.

in the same manner other 20-cyclic ketals of 3- etherified 11 3 acyloxy 3,l7oz,21 trihydroxy 19 nor 1,3,5(10) pregnatrien 20 ones are prepared by reacting the appropriate glycol with a B-etherified 11B acyloxy 3,l7oz,2l trihydroxy l9 nor 1,3,5(10) pregnatrien 20 one, including those wherein the 3-ether radical, llfi-acyloxy radical, and 20-cyclic ketal radical are those specified in the foregoing description.

Example 2.3 methoxy 11 3,17u,21 trihydroxy 19 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal 3 methoxy 11B,17a,21 trihydroxy 19 nor 1,3,5 (10) pregnatrien 20 one is converted to its 20- ethylene ketal by reaction with ethylene glycol following the procedure of Example 1. The 3 methoxy 11|B,17X,21 trihydroxy l9 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal product melts at 179 to 181 degrees centigrade.

In the same manner other 20-cyclic ketals of 3-etherified 3,11/3,17 a,21 tetrahydroxy 19 nor 1,3,5(10) pregnatrien 20 ones are prepared by reacting the appropriate glycol with a 3 etherified 3,11fi,l7a,21 tetrahydroxy 19 nor 1,3,5 (10) pregnatrien 20 one, in-

eluding those wherein the 3-ether radical and 20-cyclic ketal radical are those specified in the foregoing de-- scription.

A solution of 200 milligrams of 3 methoxy llfi acetoxy 17,21 dihydroxy 19 nor 1,3,5 (10) pregnatrien 20 one 20 ethylene ketal in twenty milliliters of benzene is added slowly with stirring to 400 milligrams of lithium aluminum hydride dissolved in 75 milliliters of dry ether. The resulting reaction mixture is stirred for one hour at room temperature (20 to 30 degrees centigrade) and ten milliliters of water then is added cautiously. The organic layer is separated and the solvent evaporated to provide 184 milligrams of crystals. Recrystallization of the crystals from ethyl acetate provides milligrams of 3 methoxy 1l/3,17a,21 trihydroxy 19 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal, melting point 178 to 180 degrees centigrade, [0:1 is plus 94 degrees in acetone. The product is identical with the product of Example 2.

Analysis.-Calculated for C H O C, 68.29; H, 7.98. Found: C, 68.48; H, 7.92.

In the same manner other 20-cyclic ketals of 3-etherified 3,l1/3,17a,21 tetrahydroxy l9 nor 1,3,5(10) pregnatrien 20 ones are prepared by reductively hydrolyzing a 3 etherified 11B acyloxy 3,l7a,21 trihydroxy 19 nor 1,3,5 (10) pregnatrien 20 one 20 cyclic ketal wherein the 3-ether, llfl-acyloxy, and 20-cyclic ketal radicals are those specified in the foregoing description.

Example 4.-3 methoxy ]1]3,17oz,2.l trihydroxy 19 nor 2,5 (10) pregnadien 20 one 20 ethylene ketal A solution of 185 milligrams of 3 methoxy 11/8,17a,21 trihydroxy 19 nor 1,3,5(10) pregnatrien 20 one 20 ethylene ketal in five milliliters of dioxane, 1.5 milliliters of ethanol and thirty milliliters of liquid ammonia is prepared and milligrams of lithium is added in small portions. The ammonia is evaporated and water is added to the residue. Filtration provides 190 milligrams of product melting at to degrees centigrade. Recrystallization of the product from ethyl acetate provides 3 methoxy 11fi,17a,2l trihydroxy 19 nor 2,5(10) pregnadien 20 one 20 ethylene ketal melting at 189 to 197 degrees centigrade.

Analysis.-Calculated for C H O C, 67.95; H, 8.43- Found: C, 67.70; H, 8.60.

Other 3 etherified 3,11fi,17u,21-- tetrahydroxy 19 nor 2,5(10) pregnadien 20 one 20 cyclic ketals are prepared in the same manner by reducing a S-etherified 3,11j3,17a,21 tetrahydroxy l9 nor 1,3,5(10) pregnatrien 20 one 20 cyclic ketal, wherein the 3-ether and 20-cyclic ketal radicals are those specified in the foregoing description.

Example 5 .-'1 1 [3,1711,21-trihydr0xy-19-n0r-5 (10) pregnene-3,20-dione 20-ethylene ketal Analysis-Calculated for C H O C, 67.32; H, 8.22. H

Found: C, 67.22; H, 8.21. I Other 1 118,17a,21-trihydroxy-19-nor-5( 10) -pregnene.-3,

' 20-dione 20-cyclic ketals are prepared in the 7 ner by hydrolysis of a 3,-etherified 3,1 1}8,l7a,21-tetrahydroxy-19-nor-2,5 (l)-pregnadien-20-one 20-cyclic ketal wherein the 3-ether and 20-cyclic ketal radicals are those specified in the foregoing description.

Example 6.-11fl,17a,21-trihydroxy-I9-n0r-4-pregnene- 3,20-a'i0ne 20-ethylene Item! A solution of 55 milligrams of l1fi,17a,2l-trihydroxy- 19-nor-5-(l0)-pregnene-3,20-ethylene ketal in fifty milliliters of methanol is prepared and forty drops of 2.5 percent sodium methoxide in methanol solution is added. The reaction mixture is maintained at room temperature -(e.g. 26 degrees centigrade) under a nitrogen atmosphere for twenty minutes. The solution then is neutralized with dilute sulfuric acid and the solvent evaporated. The residue is extracted with methylene chloride which solution is chromatographed over magnesium silicate (Florisil) using acetone-hexane (Skellysolve B) for elution to provide 35 milligrams for crystalline 11/8,17a,21-trihydroXy-19-nor-4-pregnen 3,20 dione 20 ethylene ketal; melting point 225 to 230 degrees centigrade.

In the same manner other 20-cyclic ketals of 115,170, 21-trihydroxy-l9-nor-5( -pregnene-3 ,20-dione are isomized to provide other -cyclic ketals of 1l/3,l7a,21-tri hydroxy-l9-nor-4-pregnene-3,20-dione wherein the 20- cyclic ketal radicals are those specified in the foregoing description.

Example 7.19-n0rhydrocortisone Thirty-five milligrams of 11;3,17u,21trihydroxy-19- nor-4-pregnene-3,20-dione 20-ethylene ketal is dissolved in six milliliters of fifty percent aqueous acetic acid solution and heated under refiux for 1.5 hours. The resulting solution is neutralized with potassium bicarbonate and extracted with methylene dichloride. Evaporation of the methylene chloride solvent provides 26 milligrams of 19- norhydrocortisone. Recrystallization from acetone provides purified compound; melting point 250 to 257 degrees centigrade.

Analysis.Calculated for C H O C, 68.94; H, 8.10. Found: C, 69.21; H, 8.24.

Other 20-cyclic ketals of l15,l7a,2l-trihydroxy-l9-nor- 4-pregnene-3,20-dione, wherein the 20-cyclic ketal radicals are those specified in the foregoing description, are hydrolyzed to l9-norhyclrocortisone in the same manner.

Example 8.19-norhyzir0cortisone A solution of 428 milligrams of crude 3-methoxy-1lt3, 17a,21-trihydroXy-19-nor2,5 l0) -pregnadien-20-one 20- ethylene ketal in twenty milliliters of fifty percent aqueous acetic acid solution is heated under reflux for one hour. The acid then is neutralized with potassium bicarbonate and the neutralized solution extracted with methylene chloride. Evaporation of the solvent provides 301 milligrams of crude 19-norhydrocortisone. Recrystallization from acetone provides l9-norhydrocortisone melting at 256 to 259 degrees centigrade.

Other 3-etherified 3,1 1fi,'1-'lu.,2l-tetrahdyroxy-l9-nor-2; 5(10) -preg dien-20-one 20-cyclic ketals, wherein the 3- ether and 20-cyclic ketal radicals are those specified in the foregoing description, are converted to l9-norhydrocortisone in the same manner.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. 3-etherified 1lfi-acyloxy-3,170:,21-trihydroxy-19-nor- 1,3,5 (lO)-pregnatrien-20-one 20-cyclic ketal wherein the 3 ether, llfi-acyloxy, and 20-cyclic ketal radicals are alkoxy-alkanoyloxy, and 1,2-dihydroxyalkane radicals, respectively, each containing less than twelve carbon atoms.

2. 3-etherified 3,1l/i,1711,21-tetrahydroxy-19-nor-1,3,5- (l0)-pregnatrien-20-one 20-cyclic ketal wherein the 3- ether and ZO-cyclic ketal radicals are alkoxy and 1,2-dihydroxyalkane radicals, respectively, each containing less than twelve carbon atoms.

3. 3-etherified 3,11 fi,17a,2l-tetrahydroxy l9 nor-2,5- (l0-pregnadien-20-one ZO-cyclic ketal wherein the 3-ether and 20-cyclic ketal radicals are alkoxy and 1,2-dihydroxyalkane radicals, respectively, each containing less than twelve carbon atoms.

4. l1B,l70:,21-111'ihYd10XY-l9-I10I-5( l0) -pregnene-3,20- dione 20-cyclic ketal wherein the 20-cyclic ketal radical is a 1,2-dihydroxyalkane radical containing less than twelve carbon atoms.

5 l 1,6, :,2l-trihydroxy-19-nor-4-pregnene-3,ZO-dione 20-cyclic ketal wherein the 20-cyclic ketal radical is a 1,2- dihydroxyalkane radical containing less than twelve carbon atoms.

6. 3-methoxy 11,8 acetoxy-17a,21-dihyrdoxy-19-nor- 1,3,5( l0)-pregnatrien-20-one 20-ethylene ketal.

7. 3-methoxy-l l fl,l7rx,21-trihydroXy-19-nor-1,3,5( 10) pregnatrien-ZO-one 20-ethylene ketal.

8. S-methoxy-l1,8,l7a,2ltrihydroxy l9 nor-2,5(10)- pregnadien-ZO-one 20-ethylene ketal.

9. l1fi,17a,2l trihydroxy-19-nor-5(10)-pregnene-3,20- dione 20-ethy1ene ketal.

l0. 11fl,17a,2l-trihydroxy 19 nor-4-pregnene-3,20-dione 20-ethylene ketal.

References Cited in the file of this patent UNITED STATES PATENTS Colton Nov. 9, 1954 Djerassi July 3, 1956 Pincus et aL: The Hormones, vol. III p. 543 Academic Press Inc., New York (1955). 

1. 3-ETHERFIED 11B-IACYLOXY-3,17A,21-TRIHYDROXY-19-NOR 1,3,5,(10)-PREGNATRIEN-20ONE 20-CYCLIC KETAL WHEREIN THE 3-ETHER, 11B-ACYLOXY, AND 20-CYCLIC KETAL RADICALS ARE ALKOXY-ALKANOYLOXY, AND 1,2-DIHYDROXYALKANE RADICALS, RESPECTIVELY, EACH CONTAINING LESS THAN TWELVE CARBON ATOMS. 